The present invention relates to processes for the preparation of 3-chloromethyl-1,2,4-triazolin-5-one (I), which is useful as an intermediate in the manufacture of the pharmaceutical compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine. This compound and related compounds are described in PCT International Patent Publication WO95/16679 and U.S. Pat. No. 5,637,699.
The preparation of of 3-chloromethyl-1,2,4-triazolin-5-one (I) has been disclosed, see for example International patent specification WO01/96315, published Dec. 20, 2001, and Cowden, et al., Tetrahedron Letters, 2000, vol. 41, 8661. One of the previously reported methods for making (I) involves a one pot reaction of semicarbazide hydrochloride (III•HCl) with a methyl orthoester (II) in an alcoholic solvent.

The general process for the preparation of triazolinone (I) as conventionally described above stirs a mixture of the hydrochloride salt of semicarbazide (III•HCl) and orthester (II) at room temperature in methanol for about 3 days. The methanol is evaporated, and (I) is precipitated with toluene. This reaction, although simple and straightforward, is very time consuming for large scale or industrial use. Moreover, the inventors of the present invention noted decomposition of the orthoester (II) in studies of the reaction mixture. Attempts to elevate the temperature to accelerate the reaction increased the decomposition of (II).
It will be appreciated that compound (I) is is an important intermediate for a particularly useful and promising class of therapeutic agents. As such, optimized reaction conditions for compound (I), applicable to large scale or industrial manufacture, are highly desirable.
In accordance with the present invention, the use of alkyl or aryl sulfonic acid salts of semicarbazide (III), especially the methanesulfonic (mesylate) or para-toluenesulfonic (tosylate) salts of (III), surprisingly results in improved reaction yields, shorter reaction times, no detectable decomposition of orthoester (II), and greater purity of the final product. Moreover, by the use of sulfonic acid salts as described herein, it is possible to elevate the reaction temperature. Additionally, the reaction time is reduced considerably compared to conventional routes to triazolinone (I). Despite the aforementioned benefits of the use of sulfonic acid salts of semicarbazide (III) for this process, the use of these salts for this purpose has not previously been disclosed. Additionally, the mesylate and tosylate salts of semicarbazide (III) have not previously been disclosed in substantially pure form.
Accordingly, the present invention describes a superior method for the manufacture of 3-chloromethyl-1,2,4-triazolin-5-one (I), via a simple, short, and efficient synthesis.